title: Beta-glycosphingolipids improve glucose intolerance and hepatic steatosis of the Cohen diabetic rat.
abstract: A link between altered levels of various gangliosides and the development of insulin resistance was described in transgenic mice. Naturally occurring glycosphingolipids were shown to exert immunomodulatory effects in a natural killer T (NKT) cell-dependent manner. This study examined whether glycosphingolipid-induced modulation of the immune system may reduce pancreatic and liver steatosis and stimulate insulin secretion in the Cohen diabetes-sensitive (CDS) rat, a lean model of non-insulin-resistant, nutritionally induced diabetes. Four groups of CDS rats fed a diabetogenic diet were treated with daily intraperitoneal injections of glycosphingolipids beta-glucosylceramide, beta-lactosylceramide, a combination of both (IGL), or vehicle (PBS) for up to 45 days. Immune modulation was assessed by fluorescence-activated cell sorting analysis of intrahepatic and intrasplenic lymphocytes. Steatosis was assessed by MRI imaging and histological examination of liver and pancreas, Blood glucose and plasma insulin concentrations were assessed during an oral glucose tolerance test. Administration of glycosphingolipids, particularly IGL, increased intrahepatic trapping of CD8 T and NKT lymphocytes. Pancreatic and liver histology were markedly improved and steatosis was reduced in all treated groups compared with vehicle-treated rats. Insulin secretion was restored after glycosphingolipid treatment, resulting in improved glucose tolerance. The immunomodulatory effect of beta-glycosphingolipids improved the beta-cell function of the hyperglycemic CDS rat. Thus our results suggest a role for the immune system in the pathogenesis of diabetes in this model.
authors.affiliation: Liver Unit, Dept. of Medicine, Hebrew University-Hadassah Medical Center, PO Box 12000, Jerusalem, Israel IL-91120.
authors.forename: Ehud
authors.initials: E
authors.lastname: Zigmond
authors.forename: Sarah W
authors.initials: SW
authors.lastname: Zangen
authors.forename: Orit
authors.initials: O
authors.lastname: Pappo
authors.forename: Miriam
authors.initials: M
authors.lastname: Sklair-Levy
authors.forename: Gadi
authors.initials: G
authors.lastname: Lalazar
authors.forename: Lydia
authors.initials: L
authors.lastname: Zolotaryova
authors.forename: Itamar
authors.initials: I
authors.lastname: Raz
authors.forename: Yaron
authors.initials: Y
authors.lastname: Ilan
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D005234:Fatty Liver / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D005434:Flow Cytometry; D018149:Glucose Intolerance / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D005951:Glucose Tolerance Test; D005963:Glucosylceramides / Q000494:pharmacology*; D006651:Histocytochemistry; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology; D007790:Lactosylceramides / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D005963:Glucosylceramides; D007328:Insulin; D007790:Lactosylceramides; D014280:Triglycerides